PROJECT SUMMARY Radiation therapy is the most important contributor to late toxicity in children. Unlike in adults, there is not much data on three-dimensional (3D) normal tissue radiation tolerance in children. This retrospective dosimetry study will use the patient-matched NCI computational pediatric phantom model for conducting Monte Carlo dosimetry analysis. This study will be performed on matched phantoms of all 5000 children with Wilms tumor (WT) who received radiation therapy (RT) on five National Wilms Tumor Study (NWTS) protocols during 1969-2002. The high survivorship (90%) of WT and the many advantages of the NWTS late effects database makes this an ideal platform for a detailed dosimetry study of late effects of therapy. One patient-matched phantom based on height, weight, age and sex of each NWTS patient, with already pre-contoured target organs will be selected from the phantom library of Dr. Lee at the NCI. This phantom will be imported into the radiation treatment planning system for reconstruction of NWTS radiation fields. While modern RT treatment planning systems (TPS) are fairly accurate for estimating doses both in-field and near-field locations, this method is not suitable for out-of-field dose measurements. The Monte Carlo (MC) dose calculation algorithm has overcome this deficiency of TPS and measures out-of-field doses more accurately. In this study, both dosimetry models will be used for estimating doses in-field, and MC-based dose calculations will be used for estimating out-of-field doses. For AIM 1 of this study, we will collect target organ 3D dosimetry data for 13 organs including thyroid, heart (total heart, ventricles and myocardium), lungs, kidneys, liver, chest wall, stomach, colon, breasts, uterus, ovaries, pelvis and testicles. For AIM 2 we will review and validate reproductive late effects (hypogonadism and infertility) among males and females recorded in the NWTS database and conduct a prospective questionnaire-based cohort study to determine their prevalence among NWTS survivors. For AIM 3 we will study the association between RT dose to target organs estimated using the NCI Phantom MC dosimetry model and six late effects ascertained by the NWTS including: congestive heart failure (heart, ventricles, myocardium), restrictive pulmonary disease (lungs, chest wall), second malignant neoplasms (lung, thyroid, breasts, liver stomach, colon), end stage renal disease (kidney/s), adverse pregnancy outcomes (ovaries, uterus, pelvis) and additional reproductive outcomes (hypogonadism and infertility ? ovaries, uterus in females and testicles in males). A comprehensive knowledge of 3D organ tolerance will help reduce the incidence of RT induced late toxicity and minimize their adverse impact on current and future childhood cancer survivors.